Potential and Challenges: Tirzepatide in the Treatment of Obesity

Introduction

Obesity is a chronic disease associated with an increased risk of more than 200 complications that impair health and shorten life expectancy, including many cardiovascular diseases and type 2 diabetes. With the alarming spread of the obesity epidemic, therapies based on incretin hormones have marked a major advance in treatment. These therapies harness the body’s natural hormonal response to food intake, focusing primarily on enhancing the effects of incretins—hormones that stimulate insulin secretion after meals. They positively affect appetite regulation and energy balance, which are key problems in obese individuals. Drugs such as GLP-1 (glucagon-like peptide-1) receptor agonists—including liraglutide, semaglutide, and the newer addition tirzepatide—have demonstrated significant efficacy in weight reduction and glucose control, representing an important breakthrough in therapy.

For individuals with overweight or obesity requiring pharmacological treatment, the choice of drug depends on patient preference, comorbidities, and drug availability. Clinical guidelines recommend incretin-based therapy as first-line treatment, where available. A holistic approach, including pharmacotherapy, balanced diet, and physical activity, is strongly advised.

The European Medicines Agency (EMA) approved tirzepatide under the brand name Mounjaro in May 2022 for the treatment of type 2 diabetes and obesity, in combination with dietary changes and increased physical activity. The U.S. Food and Drug Administration (FDA) approved tirzepatide under the name Zepbound in November 2023.

In Croatia, the Health Insurance Fund (HZZO) currently reimburses GLP-1 agonists only for the treatment of type 2 diabetes. Tirzepatide is not included in the HZZO reimbursement list.

How does tirzepatide work?

Tirzepatide is a long-acting dual agonist of the glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors, which are present in pancreatic α and β cells, the heart, blood vessels, immune cells, intestines, kidneys, and in brain regions important for appetite regulation. It reduces food intake and enhances satiety.

It is administered subcutaneously once weekly, starting with 2.5 mg for 4 weeks, followed by 5 mg weekly, and may be increased by 2.5 mg increments every 4 weeks up to a maximum of 15 mg weekly.

Clinical trials: efficacy of tirzepatide

Two randomized, double-blind, placebo-controlled trials in adults with obesity showed weight loss of 12% to 18% with 15 mg weekly (SURMOUNT-1 and SURMOUNT-2). More than 80% of participants lost at least 5% of body weight, compared to 35% in the placebo group. Side effects were mild and mostly gastrointestinal.

The SURMOUNT-3 trial demonstrated an additional weight reduction of 18.4% with tirzepatide compared with a 2.5% weight gain with placebo, following intensive lifestyle interventions that had already achieved ≥5% weight loss before randomization. SURMOUNT-4, an open-label study, reported a 20.9% weight loss over 36 weeks with maximum tolerated doses of tirzepatide (10 mg or 15 mg sc weekly). After randomization, those continuing tirzepatide lost an additional 5.5% of body weight, while those switched to placebo regained 14%, reversing improvements in cardiovascular risk factors.

A meta-analysis of 6 randomized controlled trials found tirzepatide 5 mg, 10 mg, and 15 mg to be more effective than placebo, with mean weight changes of –7.7 kg, –11.6 kg, and –11.8 kg, respectively (–8.1%, –11.9%, –12.4%).

The SURPASS trial showed significantly greater weight reduction with tirzepatide compared to semaglutide after 40 weeks: –1.9 kg (5 mg), –3.6 kg (10 mg), and –5.5 kg (15 mg) versus semaglutide 1 mg sc. The primary endpoint was HbA1c reduction, in which tirzepatide was both non-inferior and superior to semaglutide. However, the semaglutide dose used was lower than the maximum approved dose (2.4 mg sc), which likely underestimates semaglutide’s potential efficacy.

GLP-1 agonists have consistently shown reductions in atherosclerotic cardiovascular risk. However, cardiovascular benefit with tirzepatide has not yet been proven. The ongoing SURPASS-CVOT trial is comparing cardiovascular event rates between tirzepatide and dulaglutide in adults with type 2 diabetes and established cardiovascular disease, with results expected no earlier than October 2024.

Safety of tirzepatide

The adverse effect profile of tirzepatide is similar to that of GLP-1 agonists. The most commonly reported side effects were gastrointestinal and increased heart rate, usually mild to moderate and dose-dependent. Unlike selective GLP-1 agonists, tirzepatide has also been associated with elevated pancreatic enzymes and occasional increases in serum calcitonin. Current studies are too short to rule out potential risks of pancreatic or thyroid cancers.

Tirzepatide is contraindicated in pregnancy and in individuals with a history of medullary thyroid carcinoma or multiple endocrine neoplasia (MEN2A or MEN2B). Routine calcitonin monitoring or thyroid ultrasound is not required. Patients should be monitored for depression and suicidal ideation.

Long-term safety data remain insufficient, especially given the likelihood of lifelong use in obesity management.

Economic challenges

The high cost of tirzepatide and other GLP-1 agonists may limit widespread use, although pharmacoeconomic studies suggest they are cost-effective due to significant health benefits of weight reduction.

According to the Croatian Agency for Medicinal Products and Medical Devices, the maximum approved price of Mounjaro (tirzepatide) is €360.96 per pack for 10 mg, 12.5 mg, and 15 mg, and €199.08 for 2.5 mg. Since tirzepatide is given as a weekly subcutaneous injection, the monthly cost of treatment is at least €1,443.84.

Place of tirzepatide in obesity treatment

Incretin-based obesity therapies such as tirzepatide are highly effective, but their long-term benefit depends on continuous treatment. This is not surprising, given that obesity is a chronic, relapsing disease requiring lifelong management.

The efficacy of tirzepatide compared with GLP-1 agonists is likely similar. The only head-to-head trial used lower semaglutide doses (1 mg vs 2.4 mg sc), limiting firm conclusions. Evidence on long-term safety and cardiovascular protection remains lacking.

At present, the role of tirzepatide—especially compared to GLP-1 agonists—cannot be definitively determined.

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